The present invention is related to novel compounds, to a process for their preparation, their use and pharmaceutical compositions comprising the novel compounds. The novel compounds are useful in therapy, and in particular for the treatment of pain.
The xcex4 receptor has been identified as having a role in many bodily functions such as circulatory and pain systems. Ligands for the xcex4 receptor may therefore find potential use as analgesics, and/or as antihypertensive agents. Ligands for the xcex4 receptor have also been shown to possess immunomodulatory activities.
The identification of at least three different populations of opioid receptors (xcexc, xcex4 and xcexa) is now well established and all three are apparent in both central and peripheral nervous systems of many species including man. Analgesia has been observed in various animal models when one or more of these receptors has been activated.
With few exceptions, currently available selective opioid xcex4 ligands are peptidic in nature and are unsuitable for administration by systemic routes. Some non-peptidic xcex4 antagonists have been available for some time (see Takemori and Portoghese, 1992, Ann. Rev. Pharmacol. Tox., 32: 239-269. for review). These compounds, e.g. naltrindole, suffer from rather poor (i.e.,  less than 10-fold) selectivity for the xcex4 receptor vs. xcexc receptor binding and exhibit no analgesic activity, a fact which underscores the need for the development of highly selective non-peptidic xcex4 ligands.
Thus, the problem underlying the present invention was to find new compounds having improved analgesic effects, but also with an improved side-effect profile over current xcexc agonists and potential oral efficacy.
Analgesics that have been identified and are existing in the prior art have many disadvantages such as that they suffer from poor pharmacokinetics and are not analgesic when administered by systemic routes. Also, it has been documented that preferred compounds, described within the prior art, show significant convulsive effects when administered systemically.
The problem mentioned above has been solved by developing novel compounds which possess a piperidine ring with an exocyclic double bond, as will be described below.
The novel compounds according to the present invention are defined by the general formula (I) 
wherein
R1 is selected from
hydrogen, a branched or straight C1-C6 alkyl, C1-C6 alkenyl, C3-C8 cycloalkyl,
C4-C8(alkyl-cycloalkyl) wherein alkyl is C1-C2 alkyl and cycloalkyl is C3-C6 cycloalkyl;
C6-C10 aryl; or heteroaryl having from 5 to 10 atoms selected from any of C, S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents independently selected from any of hydrogen, CH3, xe2x80x94(CH2)pCF3, halogen, xe2x80x94CONR5R4, xe2x80x94COOR5, xe2x80x94COR5, xe2x80x94(CH2)pNR5R4, xe2x80x94(CH2)pCH3, xe2x80x94(CH2)pSO2R5, xe2x80x94(CH2)pSO2R5, and xe2x80x94(CH 2)pSO2NR5R4, wherein R4 and R5 are each and independently as defined for R1 above and p is 0, 1 or 2;
(C1-C2 alkyl)-(C6-C10 aryl); or (C1-C2 alkyl)heteroaryl, the heteroaryl moieties having from 5 to 10 atoms selected from any of C, S, N and O, and where the aryl or heteroaryl may optionally and independently be substituted by 1 or 2 substituents independently selected from any of hydrogen, CH3, xe2x80x94(CH2)qCF3, halogen, xe2x80x94CONR5R4, xe2x80x94COOR5, xe2x80x94COR5, xe2x80x94(CH2)qNR5R4, xe2x80x94(CH2)qCH3, xe2x80x94(CH2)qSOR5 xe2x80x94(CH2)qSO2R5, xe2x80x94(CH2)qSO2NR5R4 and xe2x80x94(CH2)pOR5, wherein R4 and R5 are each and independently as defined for R1 above and q is 0, 1 or 2; and 
wherein R18, R19, R20, R21, R22, R23, R24 and R25 is each and independently hydrogen
C1-C6 alkyl or C1-C6 alkenyl;
R2 and R3 is each and independently hydrogen or C1-C6 alkyl;
A is selected from 
wherein R8, R9, R10, R11, R12, R13, R14, R15, R16 and R17 are each and independently as defined for R1 above, and wherein the phenyl ring of each A substituent may be optionally and independently substituted at any position of the phenyl ring by 1 or 2 substituents Z1 and Z2 which are each and independently selected from hydrogen, CH3, xe2x80x94(CH2)qCF3, halogen, xe2x80x94CONR6R7, xe2x80x94COOR6, xe2x80x94COR6, xe2x80x94(CH2)rNR6R7, xe2x80x94(CH2)rCH3, xe2x80x94(CH2)rSOR6, xe2x80x94(CH2)rSO2R6 and xe2x80x94(CH2)rSO2NR6R7 wherein R6 and R7 are each and independently as defined for R1 above and r is 0, 1, or 2;
Q is C5-C6 hydroaryl or heterohydroaromatic having 5 or 6 atoms selected from anyone of C, S, N and O; C5-C6 cykloalkyl, or heterocycloalkyl having 5 or 6 atoms selected from anyone of C, N, O and S; and where each Q may optionally be substituted by a substituent Z1 and Z2 as defined above;
B is a substituted or unsubstituted aromatic, heteroaromatic, hydroaromatic or heterohydroaromatic moiety having from 5 to 10 atoms selected from any of C, S, N and O, optionally and independently substituted by 1 or 2 substituents independently selected from hydrogen, CH3, xe2x80x94(CH2)tCF3, halogen, xe2x80x94(CH2)tCONR5R4, xe2x80x94(CH2)tNR5R4,
xe2x80x94(CH2)tCOR5, xe2x80x94(CH2)tCOOR5, xe2x80x94OR5, xe2x80x94(CH2)tSOR5, xe2x80x94(CH2)tSO2R5, and
xe2x80x94(CH2)tSO2NR5R4, wherein R4 and R5 is each and independently as defined for R1 above, and t is 0, 1, 2 or 3; and
R4 and R5 is each and independently as defined for R1 above.
Within the scope of the invention are also pharmaceutically acceptable salts of the compounds of the formula (I), as well as isomers, hydrates, isoforms and prodrugs thereof.
Preferred compounds according to the invention are compounds of the formula (I) wherein
A is selected from 
wherein R8, R9, R10, R11, R12, R13, R14, R15, R16 and R17 is each and independently as defined for R1 above, and wherein the phenyl ring of each A substituent may be optionally and independently substituted at any position of the phenyl ring by 1 or 2 substituents Z1 and Z2 which are each and independently selected from hydrogen, CH3, xe2x80x94(CH2)qCF3, halogen, xe2x80x94CONR6R7, xe2x80x94COOR6, xe2x80x94COR6, xe2x80x94(CH2)rNR6R7, xe2x80x94(CH2)rCH3(CH2)rSOR6, xe2x80x94(CH2)rSO2R6 and xe2x80x94(CH2)rSO2NR6R7 wherein R6 and R7 is each and independently as defined for R1 above, and r is 0, 1, or 2;
Q is selected from morpholine, piperidine and pyrrolidine;
R1, R4, and R5 are each and independently selected from hydrogen, a branched or straight C1-C4 alkyl, C3-C5 cycloalkyl, C4-C8 (alkyl-cycloalkyl) wherein alkyl is C1-C2 alkyl and cycloalkyl is C3-C6 cycloalkyl; C6-C10 aryl; and heteroaryl having from 5 to 6 atoms selected from any of C, S, N and O; and where the aryl or heteroaryl may optionally and independently be substituted by 1 or 2 substituents independently selected from any of hydrogen, CH3, xe2x80x94(CH2)pCF3, halogen, xe2x80x94CONR5R4, xe2x80x94COOR5, xe2x80x94COR5, xe2x80x94(CH2)pNR5R4, xe2x80x94(CH2)pCH3, xe2x80x94(CH2)pSOR5, xe2x80x94(CH2)pSO2R5, and xe2x80x94(CH2)pSO2NR5R4, wherein R4 and R5 are each and independently as defined for R1 above and p is 0, 1 or 2;
B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, pyrryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, pyrrolidinyl, and indazolinyl, each optionally and independently substituted by 1 or 2 substituents independently selected from hydrogen, CH3, CF3, halogen, xe2x80x94(CH2)qCONR5R4, xe2x80x94(CH2)qNR5R4, xe2x80x94(CH2)qCOR5, xe2x80x94(CH2)qCO2R5, and xe2x80x94OR5, wherein q is 0 or 1, and wherein R4 and R5 are as defined above;
R2 and R3 is each and independently hydrogen or methyl.
Especially preferred compounds according to the invention are compounds of the formula (I) wherein
A is 
wherein R8 and R9 are both ethyl, and where the phenyl ring optionally and independently may be substituted at any position of the phenyl ring by 1 or 2 substituents Z1 and Z2 which are each and independently selected from hydrogen, CH3, xe2x80x94(CH2)qCF3, halogen, xe2x80x94CONR6R7, xe2x80x94COOR6, xe2x80x94COR6, xe2x80x94(CH2)rNR6R7, xe2x80x94(CH2)rCH3, xe2x80x94(CH2)rSOR6, xe2x80x94(CH2)rSO2R6 and xe2x80x94CH2)rSO2NR6R7 wherein R6 and R7 are each and independently as defined for R1 above and r is 0, 1, or 2;
R1 is selected from hydrogen, methyl, ethyl, xe2x80x94CH2CHxe2x95x90CH2, xe2x80x94CH2-cyclopropyl, xe2x80x94CH2-aryl, or CH2-heteroaryl, the heteroaryl moieties having from 5 to 6 atoms selected from any of C, S, N and O;
B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, and indazolinyl, each optionally and independently substituted by 1 or 2 substituents independently selected from hydrogen, CH3, CF3, halogen, xe2x80x94(CH2)qCONR5R4, xe2x80x94(CH2)qNR5R4, xe2x80x94(CH2)qCOR5, xe2x80x94(CH2)qCO2R5, and xe2x80x94OR5, wherein q is 0 or 1, and wherein R4 and R5 are as defined above;
R2 and R3 is each and independently hydrogen or methyl.
The substituents A and B respectively, may optionally be substituted at any position of the ring.
By xe2x80x9chalogenxe2x80x9d we mean chloro, fluoro, bromo and iodo.
By xe2x80x9carylxe2x80x9d we mean an aromatic ring having from 6 to 10 carbon atoms, such as phenyl and naphtyl.
By xe2x80x9cheteroarylxe2x80x9d we mean an aromatic ring in which one or more of the from 5-10 atoms in the ring are elements other than carbon, such as N, S and O.
By xe2x80x9chydroaromaticxe2x80x9d we mean a partly or fully saturated aromatic ring structure having 5-10 carbon atoms in the ring.
By xe2x80x9cheterohydroaromaticxe2x80x9d we mean a partly or fully saturated aromatic ring structure in which one or more of the 5-10 atoms in the ring are elements other than carbon, such as N, S and O.
By xe2x80x9cisomersxe2x80x9d we mean compounds of the formula (I), which differ by the position of their functional group and/or orientation. By xe2x80x9corientationxe2x80x9d we mean stereoisomers, diastereoisomers, regioisomers and enantiomers.
By xe2x80x9cisoformsxe2x80x9d we mean compounds of the formula (I) which differ by their crystal lattice, such as crystalline compound and amorphous compounds.
By xe2x80x9cprodrugxe2x80x9d we mean pharmacologically acceptable derivatives, e.g. esters and amides, such that the resulting biotransformation product of the derivative is the active drug. The reference by Goodman and Gilmans, The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, xe2x80x9cBiotransformation of Drugs, p. 13-15, describing prodrugs generally, is hereby incorporated.
The novel compounds of the present invention are useful in therapy, especially for the treatment of various pain conditions such as chronic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive.
Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti-tumour agents and anti viral agents.
Compounds of the invention are useful in disease states where degeneration or dysfunction of opioid receptors is present or implicated in that paradigm. This may involve the use of isotopically labelled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).
Compounds of the invention are useful for the treatment of diarrhoea, depression, urinary incontinence, various mental illnesses, cough, lung oedema, various gastro-intestinal disorders, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.
Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care. Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anaesthetic state (eg. Amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anaesthetics, hypnotica, anxiolytics, neuromuscular blockers and opioids.
The compounds of the present invention in isotopically labelled form are useful as a diagnostic agent.
Also within the scope of the invention is the use of any of the compounds according to the formula (I) above, for the manufacture of a medicament for the treatment of any of the conditions discussed above.
A further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the formula (I) above, is administered to a patient in need of such treatment
Methods of Preparation
The compounds of the present invention may be prepared as described in the following. 
As shown in SCHEME I and II above, compounds of the formula (I) above, may be obtained by dehydration of hydroxy compounds (g) or (h), wherein R1, R2, R3, A and B are as defined in formula (I) above. Subsequent dehydration of hydroxyl compounds (g) or (h), wherein R1, R2, R3, A and B are as defined in formula (I), may be performed without solvents or in a solvent such as water, alcohols, esters, HMPA, dichloromethane, toluene, ethers, ketones, carboxylic acids or in a solvent mixture in the presence of Brxc3x8nstedt or Lewis acids such as sulphuric acid, hydrochloric acid, trifluoroacetic acid, aluminium trichloride, ZnCl2 or the like, or in the presence of metallic oxides such as Al2O3, Cr2O3, TiO2, WO3, P2O5 or the like, or in the presence of other dehydrating agents such as I2, dimethyl sulfoxide, KHSO4, CuSO4, phthalic anhydride or the like.
The substituents R1, R2 and R3 and the substituents on A and B of compound (I), as defined above, may be modified by methods known in the art and exemplfied in the literature, see e.g. Protecting groups by Green, or Modem Synthetic Reactions by House, which are well known to a person skilled in the art, after or during the preparation of (I) from (g) and (h).
As shown the route a of SCHEME I, compounds of formula (g), as described above, may be obtained by a reaction between a ketone of formula (c) wherein R1, R2 and R3 are as defined in formula (I), and a compound of formula (e) wherein A and B are as defined in formula (I), and X is a suitable group such as H, Cl, Br, I, OSO2R or the like
The reaction may be performed without solvents, or in an organic solvent such as THF. toluene, ethers, dimethylsulfoxide, or in solvent mixtures by treatment with an appropriate metal such as magnesium, lithium, zinc, copper, cerium or the like, or by treatment with a metal halide such as SmI2, CrCl2 or the like, or by treatment with an organometallic agents such as alkylmagnesium halides, alkyllithium or the like.
R1, R2 and R3 and the substituents on A and B of compounds (g), as defined above, may be modified, by methods known in the art, after or during the organometallic reactions (March, J., Advanced Organic Chemistry, 4th Ed, John Wiley and Sons, 1992).
Compounds of formula (c) and (e) may be commercially available, or prepared by methods known in the art (March, J., Advanced Organic Chemistry, 4th Ed, John Wiley and Sons, 1992).
As shown in route b of SCHEME II, compounds of formula (h), as described above, may be obtained by a reaction between a ketone of formula (i) wherein R1, R2 and R3, and B are as defined in formula (I), and an organometallic reagent of formula (j) wherein A is as defined in formula (I), and M is an appropriate metal group such as magnesium, lithium, zinc, copper, cerium or the like. The reaction may be performed without solvents, or in an organic solvent such as THF, toluene, ethers, dimethylsulfoxide, or in solvent mixtures.
As shown in route c of SCHEME II, compounds of formula (h) may also be obtained by reactions among a carbonyl compound of formula (1), wherein R1, R2 and R3 are as defined in formula (I), and X is an appropriate leaving group such as Cl, Br, OH, OR, SR, NR2, N(ORxe2x80x2)R or the like, and organometallic reagents of formula (j) and (k), wherein A and B are as defined in formula (I), and M is an appropriate metal group such as magnesium, lithium, zinc, copper, cerium or the like. The reactions may be performed without solvents or in solvents such as THF, toluene, ethers, dimethyl formamide, dioxane, dimethylsulfoxide, or in solvent mixtures.
R1, R2 and R3 and the substituents on A and B of compounds (h), as defined above, may be modified, by methods known in the art and exemplfied in the literature, see e.g. Protecting groups by Green, or Modern Synthetic Reactions by House, which are well known to a person skilled in the art, after or during the organometallic reactions.
Compounds of formula (i), (j), (k) and (l) may be commercially available, or prepared by methods known in the art (March, J., Advanced Organic Chemistry, 4th Ed, John Wiley and Sons, 1992).
As shown in SCHEME III above, compounds of the formula (I) above, may be obtained from the Suzuki coupling of vinylic halide (o) (X=Br, I) with a boronic acid, boronate ester (p), in the presence of a base such as Na2CO3, K2CO3, K3PO4, triethylamine, CsF, NaOH or alkoxides and palladium catalyst such as (PPh3)4Pd, Bis(dibenzylideneacetone)Pd(0), Pd on carbon with PPh3; Pd(II) species may also be used as a catalyst including: (PPh3)2PdCl2, 1,4-Bis(diphenylphosphinobutane)palladium(II) chloride, Palladium acetate, Bis(acetonitrile)palladium(II) chloride, dichloro[1,1xe2x80x2-bis(diphenylphosphino)ferrocene] palladium(II) and palladium acetate-tri(O-tolyl)phosphine, wherein R1, R2, R3, A and B are as defined in formula (I) above. The Suzuki coupling may be performed in toluene, xylene, anisole, DMF, THF, alcohols, ethers, water or in a solvent mixture.
Compounds or formula (p), where B is as defined in formula (I) and Z is B(OH)2 may be commercially available or prepared from the hydrolysis of a boronate ester. Compounds or formula (p), where B is as defined in formula (I) and Z is B(OR)2 (R=Me, Et), may be prepared from the reaction of a compound of formula B-M and B(OR)3 where R=Me or Et, and M is an appropriate metal group such as lithium or magnesium or the like.
Compounds of formula (p) where B is as defined in formula (I) and Z is 9-borabicyclo[3.3.1]nonane (9-BBN) may be prepared from the reaction of an alk-1-yne with borabicyclo[3.3.1]nonane.
The substituents R1, R2, R3 and the substituents on A and B of compound (I) as defined above, may be modified by methods known in the art and exemplified in the literature, see e.g. Protecting groups by Green or Modern Synthetic Reactions by House, which are well known to a person skilled in the art, after or during the preparation of (I) from (o) and (p).
As shown in SCHEME III, compounds of formula (O) wherein X is Br or I, may be prepared from the halogenation and elimination of an alkene of formula (n) wherein R1, R2, R3 and A are as defined in formula (I). The halogenation may be performed in a solvent such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or acetic acid using molecular bromine or iodine as halogenation agent. The subsequent elimination step is accomplished in a solvent such as water, alcohols, DMF, or ethers using a base such as sodium hydroxide, potassium hydroxide, metal alkoxides, or triethylamine.
As shown in SCHEME III, compounds of formula (n), as described above, may be prepared from the Wittig reaction of a ketone of formula (c), where R1, R2 and R3 are as defined in formula (I), and a reagent of formula (m) where A is as defined in formula (I) and Y is an appropriate phosphonate or phosphonium salt. The Wittig reaction may be carried out under a variety of conditions known in the art and exemplified in the literature (March, J., Advanced Organic Chemistry, 4th Ed., John Wiley and Sons, 1992).
Reagents of formula (c) and (m) may be commercially available, or prepared by methods known in the art (March, J., Advanced Organic Chemistry, 4th Ed., John Wiley and Sons, 1992).
As shown in SCHEME IV above, compounds of formula (u) may be obtained by dehydration of hydroxy compound (t) wherein R1, R2, R3, R12, R13 and B are as defined above. Dehydration step may be performed without solvent or in a solvent such as water, alcohols, esters, HMPA, dichloromethane, toluene, ethers, ketones, carboxylic acids, or in a solvent mixture in the presence of Bronstedt or Lewis acids such as sulfuric acid, hydrochloric acid, trifluoroacetic acid, aluminium trichloride, ZnCl2, or the like, or in the presence of metallic oxides such as Al2O3, Cr2O3, TiO2, WO3, P2O5 or the like, or in the presence of other dehydrating agents such as h, dimethylsulfoxide, KHSO4, CuSo4, phthalic anhydride or the like.
The substituents R1, R2 and R3 and the substituent B of compound (u) as defined above may be modified by methods known in the art and exemplified in the literature, see e.g. Protecting Groups by Green, or Modem Synthetic Reactions by House, which are well known to a person skilled in the art, after or during the preparation of (u) from (t).
As shown in SCHEME IV above, compounds of formula (t) may be obtained from compound (s) wherein R1, R2, R3, R13 and B are as defined above using alkylation reaction with alkyl halide such as MeI in presence of a base such as sodium hydroxide and a phase transfer agent such as Bu4NHSO4. Compounds of formula (s) may be prepared by a reaction between a ketone of formula (r) wherein R1, R2, R3, R13 are as defined above and an organometallic reagent of formula (k) wherein B is defined in formula (I) and M is an appropriate metal group such as magnesium, lithium, zinc, copper, cerium, or the like. The reaction may be performed without solvent or in solvents such as THF, toluene, ethers, dimethylformamide, dioxane, dimethylsufoxide, or in solvent mixtures.
The substituents R1, R2, R3, R13 of compound (s) as defined above may be modified by methods known in the art and exemplified in the literature, see e.g. Protecting Groups by Green, or Modern Synthetic Reactions by House, which are well known to a person skilled in the art, after or during the preparation of (s) from (r) and (k).
As shown in SCHEME IV, a compound of formula (r) may be obtained by reactions among a carbonyl compound of formula (I) wherein R1, R2 and R3 are as defined in formula (I) and X is an appropriate leaving group such as Cl, Br, OH, OR, SR, NR2, N(OR1)R or the like and organometallic reagent obtained by first base treatment such as NaH on compound (q) wherein R13 is as defined above followed by subsequent transmetallation using alkyl lithium such as Buli. The reaction may be performed in solvents such as THF, toluene, ethers, dimethylformamide, dioxane, or in solvent mixtures. The substituents R1, R2, R3, R13 of compound (r) as defined above may be modified by methods known in the art and exemplified in the literature, see e.g. Protecting Groups by Green, or Modern Synthetic Reactions by House, which are well known to a person skilled in the art, after or during the preparation of (r) from (q) and (l).
As shown in SCHEME IV, compounds of formula (q) may be obtained by acylation of 4-iodoaniline using either acylanhydride or acylchloride in an organic solvent such as dichloromethane. The substituent R13 of compound (q) is as defined above.
The invention will now be described in more detail by way of the following Examples, which are not to be construed as limiting the invention in any way.
A) Synthetic Scheme for the Preparation of the Compounds of Examples 1-7
The compounds of Examples 1-7 were prepared by following the procedure as is shown in Scheme 1 below. 
(i) Preparation of N-t-Butoxylcarbonyl Nxe2x80x2-methyl-Nxe2x80x2-methoxyl-isonipecotamide (Compound 2)
A mixture of ethyl isonipecotate (compound 1) (4.71 g, 30.0 mmol), di-tert-butyl dicarbonate (6.55 g, 30.0 mmol) and Na2CO3 (4.77 g, 45 mmol) in H2O-THF (90/10 mL) was refluxed for 2 h. The reaction mixture was extracted with ethyl acetate (150 mL). The organic layer was washed with brine, dried over MgSO4. Removal of solvents gave N-t-butoxylcarbonyl ethyl isonipecotate (7.67 g):
xcex4H (400 MHz, CDCl3) 1.25 (t, J=7.2 Hz, 3H), 1.45 (s, 9H), 1.62 (m, 2H), 1.87 (m, 2H), 2.43 (m, 1H), 2.84 (m, 2H), 4.02 (m, 2H), 4.13 (q, J=7.2 Hz, 2H); xcex4C-13 (100 MHz, CDCl3) xcex4: 14.0, 27.8, 28.2, 40.9, 42.9, 60.2, 79.2, 154.4, 174.2.
The above N-t-butoxylcarbonyl ethyl isonipecotate was dissolved in dry THF (60 mL) and mixed with NHMe(OMe) HCl (4.39 g, 45.0 mmol). The mixture was treated with i-PrMgCl (2.0 M in THF, 45 ml, 90 mmol) at xe2x88x9220 C. and the resulting solution was stirred for 1 hr at xe2x88x925xc2x0 C. and then quenched with aqueous NH4Cl solution and extracted with ethyl acetate (2xc3x97100 mL). The combined organic layers were washed with brine, dried over MgSO4. Removal of solvents gave N-t-butoxylcarbonyl Nxe2x80x2-methyl-Nxe2x80x2-methoxyl-isonipecotamide (compound 2) (8.0 g, 98%):
xcex4H (400 MHz, CDCl3) 1.30 (s, 9H), 1.54 (m, 4H), 2.65 (m, 3H), 3.02 (s, 3H), 3.56 (s,3H), 3.99 (brs, 2H); xcex4C-13 (100 MHz, CDCl3) xcex4: 27.7, 28.1, 32.0, 37.8, 43.1, 61.3, 79.1, 154.4, 176.0.
(ii) Preperation of 4-(4xe2x80x2-Nxe2x80x2,Nxe2x80x2-Diethylaminocarbonylbenzoyl)-N-t-butoxylcarbonylpiperidine (compound 3)
To a solution of 4-iodo-N,N-diethylbenzamide (9.09 g, 30.0 mmol) and TMEDA (6.96 g, 60.0 mmol) in dry THF (60 mL) was added t-butyllithium (35.0 mL, 1.7 M, 60.0 mmol) at xe2x88x9278xc2x0 C. After 30 min, N-t-butoxylcarbonyl Nxe2x80x2-methyl-Nxe2x80x2-methoxyl-isonipecotamide (compound 2) (8.0 g, 29.4 mmol) in THF (10 mL) was dropwise added. The reaction mixture was warmed to r.t. and then quenched with aqueous NH4Cl solution, neutralized with hydrochloric acid (concentrated, 20 mL) at 0xc2x0 C., and extracted with ethyl acetate (2xc3x97100 mL). The combined organic layers were washed with brine, dried over MgSO4. Removal of solvents gave a crude product, which was purified by silica gel column eluting with MeOHxe2x80x94CH2Cl2 (2: 98) to provide 4-(4xe2x80x2-Nxe2x80x2,Nxe2x80x2-diethylaminocarbonylbenzoyl)-N-t-butoxylcarbonylpiperidine (Compound 3) (3.15 g, 28%):
xcex4H (400 MHz, CDCl3) 1.08 (brs, 3H), 1.23 (brs, 3H), 1.43 (s, 9H), 1.61 (m, 2H), 2.89 (m, 2H), 3.20 (brs, 2H), 3.40 (m, 1H), 3.53 (brs, 2H), 4.11 (brs, 2H), 7.44 (d, J=8.0 Hz, 2H), 7.94 (d, J=8.0 Hz, 2H).
(iii) Preparation of 4-(xcex1-Hydroxyl-xcex1-(4-N-t-butoxylcarbonylpiperidinyl)-xcex1-(1-naphthyl)-methyl)-N,N-diethylbenzamide (compound 4)
To a solution of 1-bromonaphthalene (0.52 g, 2.5 mmol) in dry THF (10 mL) was added n-butyllithium (1.1 mL, 2.5 M, 2.75 mmol) at xe2x88x9278xc2x0 C. After 30 min, 4-(4xe2x80x2-Nxe2x80x2,Nxe2x80x2-diethylaminocarbonylbenzoyl)-N-t-butoxylcarbonylpiperidine (compound 3) (776 mg, 2.0 mmol) in THF (2 mL) was dropwise added. The reaction mixture was warmed to r.t. and then quenched with aqueous NH4Cl solution, and extracted with ethyl acetate (2xc3x9750 mL). The combined organic layers were washed with brine, dried over MgSO4. Removal of solvents gave a crude product, which was purified by silica gel column eluting with MeOHxe2x80x94CH2Cl2 (0.5:99.5xe2x86x925:95) to provide 4-(xcex1-hydroxyl-xcex1-(4-N-t-butoxylcarbonylpiperidinyl)-xcex1-(1-naphthyl)-methyl)-N,N-diethylbenzamide (compound 4) (760 mg, 74%):
m.p. 121-124xc2x0 C. (CH2Cl2);
xcexdmax (KBr) cmxe2x88x921 3402, 2960, 1685, 1626, 1425, 1283, 1160;
Anal. Calcd. for C32H40N2O4. 0.50H2O: C, 73.11; H, 7.86; N, 5.33.
Found: C, 72.86; H, 7.64; N, 5.26; xcex4H (400 MHz, CDCl3) 1.03 (brs, 3H), 1.16 (brs, 3H), 1.18-1.35 (m, 3H), 1.95 (m, 1H), 2.60 (m, 2H), 2.75 (brs, 2H), 3.15 (brs, 2H), 3.42 (brs, 2H), 4.10 (brs, 2H), 7.10-7.50 (m, 7H), 7.75 (m, 3H), 8.27 (brs, 1H); xcex4C-13 (100 MHz, CDCl3) xcex4: 12.8, 14.1, 27.1, 27.2, 28.4, 39.2, 43.3, 45.4, 79.3, 80.4, 124.1, 124.9, 125.2, 125.3, 126.0, 127.3, 128.8, 129.2, 131.4, 135.0, 135.2, 139.4, 146.5, 154.6, 171.0.
(iv) Preparation of 4-(xcex1-Hydroxyl-xcex1-(4-N-t-butoxylcarbonylpiperidinyl)-2,6-dimethylbenzyl)-N,N-diethylbenzamide (Compound 5)
Method as described for compound 4, except using 2-bromo-m-xylene; (749 mg, 76%):
m.p. 92-96xc2x0 C. (CH2Cl2);
xcexdmax (KBr) cmxe2x88x921 3451, 2970, 1690, 1631, 1425, 1165;
Anal. Calcd. for C30H42N2O4. 0.50H2O: C, 71.54; H, 8.61; N, 5.56.
Found: C, 71.70; H, 8.34; N, 5.62; 5H (400 MHz, CDCl3) 1.10 (brs, 3H), 1.21 (brs, 3H) 1.32 (m, 2H), 1.43 (s, 9H), 1.69 (m, 1H), 1.77 (m, 1H), 2.32 (s, 6H), 2.47 (s, 1H), 2.75 (m, 3H), 3.25 (brs, 2H), 3.51 (brs, 2H), 4.13 (brs, 2H), 6.91 (m, 2H), 7.00 (m, 1H), 7.26 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H); xcex4C-13 (100 MHz, CDCl3) xcex4: 12.6, 14.0, 25.0, 27.7, 28.2, 39.1, 42.9, 43.1, 44.4, 53.3, 79.1, 83.0, 125.8, 126.3, 127.2, 131.2, 135.3, 136.7, 142.9, 147.8, 154.5, 170.7.